Electrolytic transdermal delivery of polypeptides

ABSTRACT

The invention comprises in combination: 
     (a) a polypeptide having from about three to about 20 peptide units in aqueous solution or suspension, and 
     (b) an electrolytic device for transdermal transport of the polypeptide to the bloodstream of the patient. 
     It may be useful to enhance the transdermal delivery of the polypeptide by adding an aqueous cosolute/cosolvent with negative Setschenow constants. 
     The electrolytic device preferably comprises a hydrophilic reservoir containing a supply of the aqueous polypeptide solution or suspension, an electric battery, two extended contacts, and optionally a semipermeable membrane between the reservoir and the patient&#39;s skin. 
     Representative polypeptides include oxytocin, angiotensin I, II, and III, substance P, vasopressin, lypressin, desmopressin, leuprolide acetate, antripeptin, and the like.

RELATED U.S. PATENTS AND APPLICATIONS

This application is a continuation of application Ser. No. 360,277,filed June 1, 1989, abandoned, which is a continuation of Ser. No.012,889, filed Feb. 10, 1987, now U.S. Pat. No. 4,878,892.

This application is related to U.S. Pat. Nos. 4,557,723, 4,622,031 and4,640,689 and to copending applications Ser. No. PCT/US85/00080 filedJan. 17, 1985; PCT/US85/01074 and PCT/US85/01075 both filed June 10,1985; Ser. No. 778,183 filed Sept. 16, 1985 now U.S. Pat. No. 4,708,766;Ser. No. 807,234 filed Dec. 10, 1985 now U.S. Pat. No. 4,731,926; Ser.No. 839,523 filed Mar. 14, 1986 abandoned; Ser. No. 888,151 filed July18, 1986 abandoned; Ser. No. 922,296 filed Oct. 23, 1986 abandoned; andSer. No. 07,000,554 and 07,000,555 filed Jan. 5, 1987, now U.S. Pat. No.4,808,152 and abandoned, respectively.

FIELD OF THE INVENTION

This invention relates to electrolytic transdermal delivery ofpolypeptides and more specifically to delivery to the blood stream ofthe patient of aqueous solutions of suspensions containing polypeptideswith from about three to about 20 alphaamino acid units.

BACKGROUND OF THE INVENTION

Patents and patent applications cited above disclose basic aspects oftransdermal delivery of drugs by electrical power patches on thepatient's skin. Other U.S. and foreign patents also disclose transdermalelectrical, and medical effects, as follows:

    ______________________________________                                        U.S. Pat. Nos.                                                                385,556      2,267,162      3,163,166                                         486,902      2,493,155      3,289,671                                         588,479      2,784,715      3,547,107                                         3,677,268    4,239,052      4,367,745                                         4,008,721    4,243,052      4,367,745                                         4,141,358    4,273,135      4,406,658                                         4,164,226    4,290,878      4,419,019                                         4,166,457    4,325,367      4,474,570                                         4,239,046    4,362,645                                                        Foreign Patents                                                               EPA 58,920   DE 2,902,021.83                                                                              UK 2,104,388                                      EPA 60,452   DE 3,225,748                                                     ______________________________________                                    

None of these references, however, show the effective administration ofpolypeptide drugs such as desmopressin, vasopressin, substance P,angiotensin, lypressin and the like.

OBJECTS OF THE INVENTION

It is an object of the present invention to administer polypeptide drugswith a range of molecular weights from about three peptide units toabout 20 peptide units transdermally to humans, adult or child, andother animal patients by means of a locally applied electric field.

It is a further object of the invention to administer polypeptide drugstransdermally in an electric field regardless of the degree ofionization or the amount of ionic charge on the polypeptide.

It is yet another object to maximize the transdermal administration ofpolypeptide drugs by eliminating or minimizing the association ofpolypeptide drugs in aqueous media.

It is still another object to administer polypeptide drugs transdermallyby an electric applicator which occupies minimal area, gives the patientminimal discomfort, generates sufficient current density with minimalsize and weight, and operates effectively under a wide variety of skinconditions.

It is yet a further object to administer polypeptide drugs transdermallyby electrolytic devices without irritation or reddening of the skin, andwithout tingling or other sensations.

Other objects of the present invention will be apparent to those skilledin the art.

SUMMARY OF THE INVENTION

The present invention comprises in combination:

(a) a polypeptide having from about three to about 20 peptide units inaqueous solution or suspension, and

(b) an electrolytic device for transdermal transport of the polypeptideto the bloodstream of the patient.

The invention further comprises a method for delivering the polypeptideto the bloodstream of the patient by means of the electrolytic device.

The polypeptide may be of homopolymeric, heteropolymeric, cyclical, orother structural type.

It may be useful to enhance the transdermal delivery of the polypeptideby adding an aqueous cosolute/cosolvent with negative Setschenowconstants.

The electrolytic device preferably comprises a hydrophilic reservoircontaining a supply of the aqueous polypeptide solution or suspension,an electric battery, two extended contacts, and optionally asemipermeable membrane between the reservoir and the patient's skin.

Representative polypeptides include oxytocin, angiotensin I, II, andIII, substance P, vasopressin, lypressin, desmopressin, leuprolideacetate, and the like. Within the scope of this invention is thetransdermal delivery of polypeptides with other classes of drugs, suchas steroids.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a cross-sectional view of one type of electronic/electrolyticdevice to administer polypeptides to a patient transdermally.

DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE INVENTION

Polypeptides are condensation polymers of aminoacids which are linked byformation of amide bonds from the amino group of one aminoacid and thecarboxylic acid group of another. Polypeptides are homopolymers orheteropolymers of the 20 aminoacids necessary to build mammalian bodytissue. In nature, they have a laevo configuration. In this disclosure"polypeptide" means molecules with from about three to about 20 peptideunits or amino acids.

In copending application Ser. No. 07/012,898, filed concurrently on Feb.10, 1987 abandoned. I disclose an invention for administering "proteins"transdermally by electrolytic means and define "protein" as apolypeptide with more than about 20 peptide units, e.g. insulin whosesingle-strand has 51 units.

Numerous polypeptides are useful drugs in the treatment of humandiseases or their diagnosis. Table I shows examples of the names ofdrugs, their trade names, and their application.

                  TABLE I                                                         ______________________________________                                        Some Polypeptide Drugs                                                                            No. of                                                               Trade-   Peptide                                                   Name       name(s)  Units       Application                                   ______________________________________                                        vasopressin                                                                              Pitressin                                                                              9           diabetes insipidus                                                            GI hemmorhage                                 desmopressin                                                                             DDAVP    9           diabetes insipidus                            oxytocin   Pitocin  9           induction of labor                            lypressin  Diapid   9           antidiuretic                                  leuprolide Lupron   9           prostate cancer                               acetate                         LH-RH FSH inhibitor                           dynorphin A                                                                              (1-17)   17          peptide                                       dynorphin A                                                                              (1-8)    8           opioides                                      dynorphin B         13          are                                           met-enkephalin      5           analgesics                                    leu-enkephalin      5                                                         thyrotropin                                                                              TRH      3           clinical diagnostic                           releasing hormone                                                                        MIF      3                                                         α-melanocyte                                                                       α-MSH                                                                            13          hormonal regulator                            stim. hormone                                                                 β-melanocyte                                                                        β-MSH                                                                             18          hormonal regulator                            stim. hormone                                                                 neurotensin         13          insulin regulator                             substance P         11          analgesic                                     somatostatin        14          growth hormone inhib                          angiotensin I       10          modulate                                      II                  8           blood                                         III                 7           pressure                                      atriopeptin         21          fluid regulation                              ______________________________________                                    

It should be emphasized that polypeptides can vary widely in the numberof peptide units they contain from a few, as in thyrotropin releasinghormone to six times 51 units as in hexameric insulin. In order forlarge polypeptides to be transported through the skin, it is preferablethat the polypeptide be unassociated. If the polypeptide issingle-stranded, the cross-section of the linear macromolecular would beonly a few square Angstoms even if the entire folded, convoluted, orrandom polymer is large in radius of gyration. It is sometimespreferable to add a dissociating agent to a solution of the smallerpolypeptides of the present invention, also.

There have been many proposed descriptive models for the structure ofliquid water, such as:

(a) in interstitial model of ice whose cavities are filled with water,

(b) quartz-like aggregates,

(c) water as a hydrate of itself,

(d) flickering clusters of cooperative H-bonds;

(e) a two-structure, mixture model.

Chemists have known for decades that water forms clathrates with xenon,chlorine, methane and other molecules and therefore must have cavities.The structure of liquid water depends on the distance and angles ofH-bonds. In a two-dimensional sense, water is a hexagonal array of"aromatic" structures.

The solubility of argon in "structured" water is about one-tenth that ofargon in alcohols. As temperature increases from 0° to 30° C. thesolubility of argon in water decreases while that in alcohols increases.The charge in entropy of methane in water is about -15 to -20 e.u. butin alcohols, dioxane, and cyclohexane is about -1 e.u. The change inenthalpy of methane in water is about -3000 cal/mole, but in the sameorganics is 200-500 cal/mole. The process of solution may be modeled as"forming a cavity" then introducing the solute into that cavity. In anormal fluid the energy to form the cavity is positive, then filling thecavity is minus (attractive). Since water already has cavities present,there is about zero energy to form such and negative energy to dissolvethe solute (fill) the cavity.

Adding some nonpolar nonelectrolytes such as ether, methyl acetate,dimethylsulfoxide structure water i.e. reinforce water structure anddecrease its compressibility. Some small ions e.g. lithium and fluoridealso reinforce the structure of water.

Conversely, most ions, iodine, methyl halides, small aminoacids, urea,and other polar nonelectrolytes are "structure breakers" of water.

Precise analysis of the structure of water may be a complex matter, yetit is a description of only one substance. Precise description ofpolypeptides dissolving in water, or dissociating if already dissolved,covers much broader phenomena, since there are myriad polypeptides andmyriad cosolvents or dissociation agents to coact with water.

The conformation of polypeptides in solution is dependent at a minimumon the concentration of polypeptide, pH, solvent composition, ionicstrength, ionic charge on the polypeptide, solvent dielectricproperties, presence of cosolutes, shear stresses, and the presence ofheterogeneous third bodies such as surfaces of the container, granules,and the like.

It is generally accepted that the configuration of polypeptides inaqueous media comprises folded macromolecules with hydrophopic domainsforming a central core and hydrophilic domains oriented toward theaqueous perimeter. The process of dissolution is difficult to describein detail, but the energetics of the solution process can be determinedin a straightforward manner. Much information about solution,disassociation, denaturation, coiling, gelation, unfolding, and otherchanges in so-called tertiary and quaternary structures may be gainedfrom a detailed study of solution and/or gelation of polypeptides inwater and water containing other cosolvents or "agents".

The primary structure of a polypeptide is the term used for the sequenceof aminoacids as they appear along the chain of the macromolecule. Thelocal organization of the chain e.g. helix formation, random coil,folding is termed secondary structure. The overall spatial arrangementof the polypeptide on the atomic level, what X-ray crystallographyshows, is the tertiary level of structure. The quaternary structure isthat of several chains which may form different regions with differentproperties e.g. a dumbbell-like structure with a flexible middle rod andtwo hard ends. The function of the regions may vary. In hemoglobin, 4myoglobins group to form a dumbbell shape with a molecular weight ofabout 17,000 daltons with the oxygen-bearing function associated withthe two harder spheres on the ends rather than the flexible part in themiddle.

Dissociation agents greatly affect quaternary structure, are irrelevantto tertiary structure, may affect secondary structure, and have noeffect on primary structure of polypeptides.

The effect of a solvent such as water on a polypeptide can be describedin terms of an equilibrium constant K_(D) and the standard free energyof dissociation ΔF°, when a polypeptide dissociates from e.g. hexamersto dimers or single-stranded subunits e.g. insulin in water. Often thesedifferent fragments can coexist in a series of equilibria e.g. earthwormhemoglobin duodecamers, hexamers, tetramers, dimers, and singlefragments, at intermediate concentrations of a pure solvent or one witha dissociation agent such as propylurea or sodium perchlorate present.When such an added dissociation cosolvent is present there are twodissociation constants K_(DW) and K_(DAW), where DW designates purewater and DAW designates added agent and water. The interaction of theadded agent and the polypeptide involves the binding constant K_(B).

For polypeptides binding constant K_(B) is the summation of two terms: apolar component K_(P) related to the peptide bond --NHCOO-- and ahydrophobic component K_(H) related to the average hydrophobic moiety--CHR-- different for each aminoacid but averagable. The constant isrelated to energetics by the Nernst equation. So

    F°.sub.DW =F°.sub.DAW -mNRT (K.sub.p +K.sub.H)[da],

when m is the number of fragments and N is the number of binding sitesand [da] is the concentration of the dissociation cosolvent.

When a solid polypeptide is in contact with a well-stirred solvent suchas water for a long time (e.g. a week) an equilibrium saturated solutionis established:

    K.sub.eq =-RTlnC.sub.sat

When another compound is added to the water, such as an electrolyte or anonelectyrolyte, a different C_(sat) is established at equilibrium. Thisother value will normally be different from C_(sat) for pure water. Thehigher the concentration of the added agent, the higher (or lower) thesaturated concentration of the polypeptide. When one graphs the logC_(sat) against the molarity of the added agent, a straight line isformed. The slope of this straight line is known as the Setschenowconstant for the agent. Since the equation above has a minus sign in it,those agents which aid solubility and dissociation, e.g. urea, have anegative Setschenow constant, and those agents which decrease solubilityand dissociation, e.g. sodium or ammonium sulfate have positiveSetschenow constants.

    K.sub.s ≈-K.sub.B /2.303

The Setschenow constant K_(s) has peptide and hydrophobic components.The Setschenow constant can be approximated by negative K_(B) divided bylog transform constant 2.303. Since negative standard free energies oftransfer indicate spontaneous reactions, negative F° values for transferfrom water to a mixture of water and the cosolvent indicatedissociation. The more negative, the more dissociated. Table II givesSetschenow constants for average peptide and hydrophobic groups as wellas free energy of transfer values for a variety of cosolvents, as takenfrom a paper by Herkovits et al., Journal of Colloid and InterfaceScience, vol. 63, No. 2, p. 232 of February 1978. The lower the positionin Table II, the better the dissociation agent.

Since thermodynamics is a description of the ultimate reality, the lastcolumn listing free energies of transfer shows those agents which arepreferred in practicing the present invention, those agents withnegative standard free energies. The Setschenow constants are helpful,however, in appreciating how the agent is useful. The "sum" column ofinteraction with peptide linkages in the polypeptide plus theinteraction with the hydrophobic moieties is directly linked to the freeenergy column by the Nernst equation. It is the peptide interactionnumber and the hydrophobic or "methylene" number, which show how adissociation agent works.

                  TABLE II                                                        ______________________________________                                        Setschenow Constants                                                                                                 -F.°                            Agent       For peptide                                                                             For --CH2--                                                                              Sum   cal/mo                                 ______________________________________                                        Sodium sulfate                                                                            -0.013    0.085      0.072 98                                     Potassium fluoride                                                                        -0.027    0.05       0.023 31                                     Ethanol     +0.037    -0.014     0.023 31                                     Dioxane     +0.029    -0.013     0.016 22                                     Sodium chloride                                                                           -0.037    0.033      -0.004                                                                              -5                                     Sodium acetate                                                                            --        --         -0.009                                                                              -12                                    Sodium bromide                                                                            -0.037    0.025      -0.012                                                                              -16                                    Calcium chloride                                                                          -0.077    0.063      -0.014                                                                              -19                                    Sodium proprionate                                                                        --        --         -0.017                                                                              -23                                    Urea        -0.018    -0.01      -0.028                                                                              -38                                    Sodium butyrate                                                                           --        --         -0.038                                                                              -51                                    Propylurea  --        --         -0.047                                                                              -64                                    Sodium thiocyanate                                                                        -0.077    0.007      -0.07 -96                                    Potassium iodide                                                                          -0.083    0.01       -0.073                                                                              -100                                   Sodium perchlorate                                                                        -0.097    0.021      -0.076                                                                              -104                                   Sodium iodide                                                                             -0.087    0.01       -0.077                                                                              -105                                   Guanidine hydro-                                                                          -0.061    -0.027     -0.088                                                                              -120                                   chloride                                                                      ______________________________________                                    

Urea, guanidine hydrochloride, or any other compound which has twonegative parameters interact with the entire polypeptide to disaggregateany quaternary structure and perhaps unfold the secondary structure.This type of dissociating agent may be helpful in practicing the presentinvention of delivering polypeptides with from abaout three to about 20peptide units to the bloodstream of the patient. Sodium perchlorate,potassium iodide, and the like interact so strongly with peptide bondsthat their lack of interaction with hydrophobic linkages of thepolypeptide does not appreciably inhibit dissociation of thepolypeptide. These agents may be useful in practicing the presentinvention. Ethanol, dioxane and other organics strongly react with thehydrophobic moieties, but not enough to overcome the nonpolar nature oforganic solvents. Data on ethanol diverges, however. Such agents havelimited utility in practicing this invention. Agents which have twopositive components for their Setschenow constant and hence a positivestandard free energy of transfer do not appear on Table II.

Electrophoresis is the transport of both solute and solvent in anelectric field. Ionophoresis is the transport of charged ions bycoulombic attraction/repulsion in an electric field. Electroosmosis isthe transport of solvent in an electric field.

Many workers in the prior art overemphasized ionophoresis andunderestimated electroosmosis in their analysis of both the best modesfor and problems associated with transdermal delivery of drugs byelectrolytic means. In fact, the essence of transdermal,electric-powered delivery of drugs is that control and maximization iscentral regardless of whether the drug is transported by coulombicattraction/repulsion or electroosmotic solvent streaming. In the presentinvention, unlike the prior art, Faraday's law is irrelevant. In manysituations, more drug is carried by electroosmosis than ionophoresis, sothat the amount of charge or degree of ionization of the polypeptide isnot important. Before the present invention this fact was notappreciated. Prior workers attempted to improve ionophoresis byincreasing charge density on the polypeptide by oxidation or hydrolysis.For this invention the value of charge density on the drug does notcontrol the dosage.

Electronic conduction is the movement of electrons in an electric field.Electrolytic conduction is the movement of ions in an electric field.Prior to the present invention, many workers failed to communicate theirresults well or to explain their ideas well because of confusionregarding the flow of electrons and the flow of ions. In the applicatorof the present invention, current flow in the electrodes is electronicand current flow in the reservoir and through the skin is electrolytic,but it is possible to have some electronic flow along the chain of apolypeptide in an electric field in water or aqueous media.

The values of the electrical variables in the practice of the currentinvention in vivo are those pertaining to electroosmosis notionophoresis. The current density may range from about 0.5 ua/cm² toabout 1 ma/cm², preferably about 0.5 microampere/cm² to about 10microampere/cm² rather than 1 milliampere/cm² to 5 milliamperes/cm²values associated with ionophoresis. The voltage impressed for operatingthe applicator of the present invention ranges from about 1 to about 40volts rather than the 50 to 100 or more volts advisable forionophoresis. Likewise the migratory flow of water in an electrolyticfield are the much higher values of about 0.001 ml/cm² /hr to about0.005 ml/cm² /constant of electroosmosis not the typical adventitiousvalues for ionophoresis, following Faraday's law which impels only ions.

It is highly preferred that the current density employed in the presentinvention be low enough to prevent any irritation, reddening,inflammation, or erythema in the skin of the patient. In addition to thepolypeptide drug, there may be salts for physiological balance,buffering agents, biocides, preservatives, disinfectants, antibiotics,or other additives in the composition of the drug reservoir of theelectrolytic transdermal device.

It is sometimes useful to add chelating agents to the drug. Some of themetal ions which may be associated with the polypeptide are magnesium,zinc, copper, chromium, cobalt, nickel, iron, and manganese. Manyconventional chelating agents may be employed such as the salts ofethylenediaminetetraacetic acid (EDTA). Other conventional chelatingagents may also be used.

FIG. 1 shows generally drug applicator 10 comprising outer cover 12having a raised portion 14 and an outer-edge lip 16 in contact with theskin 18 of the patient. The layered structure of the drug applicator 10can be any convenient and effective size or shape such as rectangle,oval, circle, or splayed shape to fit crevices at interfaces of bodyparts. The size of the applicator may range from about 10 cm² to about200 cm² depending on its use and the species, age, and size of thepatient.

Applicator 10 often has generally a structure of horizontal layers. Thelayer shown in FIG. 1 as that closest to the skin 18 is an optionalsemipermeable membrane 22 through which the drug diffuses for depositionon skin 18. Optional membrane 22 may be constructed of semipermeablecellulose acetate, poly(vinyl chloride), or regenerated cellulose.

Above optional semipermeable membrane 22 is a reservoir, region, orpouch 24 for holding the supply of the drug to be electrolyticallydelivered. Preferably reservoir 24 defines a closed space and isflexible. Typical materials used in forming pouch 24 are rayon floc,polyurethane sponge, and hydrophilic adhesives. This reservoir may alsoconsist of a hydrophilic gel. For containing the polypeptide solution orsuspension of the present invention, reservoir 24 may range from about0.01 ml to about 15 ml in volume, preferably about 0.15 ml to about 0.9ml for about a week's continual administration of a polypeptide drug inamounts ranging from about 500 nanograms to 1 mg per day, depending onthe size, species, and age of the patient. The gel, pouch, or walls ofthe reservoir 24 must be microporous enough to transfer of the solvent,solution, or suspension of the polypeptide by the electric field, butnot so porous to allow leakage of the suspension or solution of thepolypeptide drug. The choice of whether or not to employ optionalsemipermeable membrane 22 is interrelated with the choice of design andmaterial of reservoir 24, because their functions may overlap.

The next higher layer above reservoir 24 as shown in FIG. 1 comprisesextended contact 26 which is preferably the lower face of battery 28.Contact 26 preferably is flexible enough to conform to the surface ofthe skin and also is electronically conductive. Preferred materials forcontact 26 are electric-conducting polymers, carbonized plastic films,or plastic surfaces loaded with highly conductive powdered or solidcarbon or graphite.

Battery 28 comprising the next layer may be made up of a group of cellsinternally connected in series to obtain the desired voltage necessaryto obtain the electrophoretic action with the particular polypeptide.Orientation of battery 28 depends on the direction of endosmotic flowwhich is usually from the anode. With regard to battery 28, it should benoted that any conventional miniaturized battery cells now generallyavailable can be employed, arranged and connected in series to obtainthe desired operating voltage. In addition, the technology now existsfor batteries made of thin, flexible sheets of an electricallyconductive polymer with high surface area relative to its thickness toprovide adequate current densities. One such so-called plastic batteryis described in "Batteries Today", Autumn 1981, pages 10, 11, and 24.When such a battery is employed, sheets may be layered to place thecells in series, and an effective compromise between number of sheetsand surface areas of sheets is achieved by layering them diagonally, asshown somewhat schematically in FIG. 1. Of course, battery selectionalso depends on such factors as the degree of conformability desired,voltage and current densities required for a specific application, andtime of discharge.

In FIG. 1, above battery 28 is electrical contact 32, which preferablyis similar in design and material to electrical contact 26 and forms theopposite side of the battery.

Cover 12 encloses all the previously listed layers of drug applicator 10and is made of flexible, conductive material such as a plastic polymerimpregnated with carbon, electrically conductive itself, or metallizedon its surface. Insulating material 34 fills the space between the sidewalls of raised portion 14 and the various aqueous layers containingelectrolyte. Suitable insulating materials are polyester, silicones, andany other drug-compatable plastics. Alternatively, a totally insulatingcover may envelope all of the working components previously named.

In order for drug applicator 10 to make good contact with and stick tothe patient's skin 18 electrically-conductive adhesive 36 is appliedunder the edge of lip 16. Suitable conducting adhesive materials arethose filled with powdered conductors such as carbon or graphite.

It will be seen that the arrangement described above forms a completeelectric circuit from one side of battery 28, cover 12, adhesivematerial 36, skin 18, microporous membrane 22, liquid reservoir 24, andback to battery 28. Also, the reservoir may be divided into separateanode and cathode compartments with an insulator between and the batteryin a separate compartment.

The electrical operation of the drug applicator may be carried out inmany modes, including that of uniform direct current. The impressedvoltage from the power source may be pulsed with a wide variety of pulsewidth and frequency. A sawtooth voltage or other types of reversing,sinusoidal, or alternating voltage sources are also within thedisclosure of this invention.

The types of batteries and their orientation are disclosed inter alia inU.S. Pat. Nos. 4,557,723 and 4,640,689. The types of circuits which maybe employed are also disclosed in various of the above-cited relatedapplications.

Table I shows some of the therapeutic polypeptides with commercial orexperimental status. The evolutionary relationships, aminoacidsequences, intra- and interrelationships, structures, and activity ofpolypeptide hormones and drugs are generally known and published. Theseventh edition of Goodman and Gilman's "The Pharmacological Basis ofTherapeutics", Macmillan, N.Y., 1985 has relevant material. Also see40th edition of "Physicians' Desk Reference", Medical Economics Co.,Oradell, N.J., 1986.

The present invention encompasses the electrolytic transdermal deliveryof solutions and suspensions of the numerous polypeptide drugs,hormones, agonists, secretion inhibitors, and regulators of glucosemetabolism, water regulation, CNS activity, growth, pain alleviation,blood pressure regulation, cancer alleviation, and other functions formolecules having from about three (cf. thyrotropin releasing hormone) toabout 20 (cf. atriopeptin, said to be 21) peptide units. Without beinglimited by theory, it is believed that the primary mechanism for thiselectrolytic delivery is by electroosmosis, not ionophoresis, aserroneously subscribed to by the scientific workers in the prior art.

In many cases it is preferred to add cosolvent/cosolute molecules withnegative Setschenow constants to the polypeptide drugs of the presentinvention to facilitate their transdermal delivery, as shown in TableII.

Having described the inventive composition of polypeptide, waterstructure-breaking solute, and aqueous electrolyte and having describedthe preferred embodiment of the electrolytic drug applicator fortransdermal delivery of polypeptides, we now illustrate the invention inthe following Examples. These Examples, however, are intended only toillustrate not limit the scope of the instant invention, which may becarried out by other means and still be covered by the teachings of thisdisclosure.

EXAMPLE 1

This Example illustrates the preparation of small electrolytictransdermal devices with side-by-side reservoirs and electrodes. Anotherpossible design is that of a "matted-photograph" with the drug reservoiranode surrounded by an insulated frame-shaped cathode, as shown in FIG.1.

The side-by-side reservoirs and electrodes have a rayon gauze next tothe skin (Johnson & Johnson Co., New Brunswich, N.J.). Two matted rayonpads 5 cm×8 cm×0.5 cm are topped by U-shaped polyester film 0.1 mm thickcoated with 0.02 mm layer of conducting graphite paint (Bertek Corp.,St. Albans, Vt.) surrounding a central insulator of 0.2 mm Mylarpolyester film (duPont Co., Wilmington, Del.). The top surface of theU-shaped graphitized polyester film is connected to a 9 V battery (ElPower Corp., Santa Anna, Calif.). The periphery of the felted reservoirpads and electrodes plus an insulating band in the gauze base betweenthem is RTV silicone resin (Dow Corning Co., Midland, Mich.).Surrounding the top and side of the device is surgical adhesive tape(Hy-Tape Surgical Hosiery Corp., New York, N.Y.). Each of the reservoirscan hold 6 ml of aquesous fluid.

EXAMPLE 2

This Example illustrates the use of the present invention to delivertherapeutic amounts of an experimental linear polypeptide having aboutten peptide units, useful in the treatment of prostate cancer, compoundDUA, a variant of leuprolide acetate.

Four male subjects were fitted: two with large drug applicators (9 cm by13 cm) active area 37 cm² on the chest, subjects A and B, and two withsmall drug applicators (5 cm by 13 cm) active area 11 cm² on the volararea of the arm, subjects C and D. The large applicators had reservoirsof 0.6 ml; the small 0.15 ml. The solution in the reservoir consisted of10 percent polypeptide and 1 percent urea.

The battery had a voltage of 9 volts; the current density was 3.5microamperes/cm² for the application time of eight hours. During thattime the polypeptide was transdermally transported to the extent of 200microgr./hr for the large and 60 microgr./hr for the small applicators.Blood analysis shows the amount and activity of the delivered hormone inthe hormonal response to the delivery of the drug to the four subjects,as follows:

A a five-fold increase in 3 hrs.,

B a four-fold increase in 4 hrs.,

C a triple response in 5 hrs.,

D a 12-fold increase within 6 hrs.

This stimulated response of the subjects is typical of a healthy, adult,male receiving therapeutic subcutaneous bolus injection of this hormone.

MODEL EXAMPLE 1

This Model Example illustrates the application of the present inventionto the delivery of lypressin (Diapid, Sandoz Co., East Hanover, N.J.) tothe bloodstream of the patient.

Eight beagle dogs are employed. All of them are clipped on the back,washed with castille soap, and fitted with the small animal electrolyticpatches of Example 1, four of them without batteries.

The drug reservoir of each patch contains 6 ml. Diapid 50 USP, 0.185 mglypressin/ml. The return reservoir contains 0.9 percent saline. Acurrent regulator is set to deliver 10 ua/cm².

Over a period of ten days the total urine output of each dog is measuredby standard techniques. It is found that the average total urine volumeof the four dogs wearing the powered device of the present invention issignificantly lower than that of the average of the four control dogs.

MODEL EXAMPLE 2

This Model Example illustrates the use of the present invention todelivery vasopressin for the treatment of diabetes insipidus.

Six adult male volunteers each having been diagnosed as having diabetesinsipidus are tested. Three are fitted with the large-size human patch,as in Example 2, and the three controls are fitted with drug-loaded,identical patches without batteries.

The drug reservoirs of the large electrolytic patches contain 15 ml (300units) of Pitressin (Parke-aDavis Co., Morris Plains, N.J.). The returnreservoir contains 0.9 percent saline buffered to pH 7.2 with ammoniumdihydrogen phosphate.

Urine samples are taken from each subject three times per day for fivedays. It is found that the electrical conductivity of the urine of thesubjects wearing the powered Pitressin (vasopressin) electrolyte patchesaverages significantly higher than that of the three control subjects,showing higher electrolyte content.

MODEL EXAMPLE 3

This Model Example illustrates the use of the present invention todeliver atrial natiuretic factor, atriopeptin, directly to thebloodstream of patients.

Ten adult female volunteers, diagnosed as having hypertension, arechosen for this experiment. All are fitted with the large-sizeelectrolytic transdermal patch, as in Example 2.

The subjects are fitted with patches of the present invention having adrug reservoir containing 5 ml of a 0.01M solution of atriopeptin in0.1M sodium perchlorate, a salt with negative Setschenow constants. Fivecontrol patches have no batteries. The regulated power source is set togive a current density of about 10 ua/cm², delivering about 200nanograms of drug per hour.

The blood pressure of the ten subjects is measured four times a day. Itis found that the average blood pressure of the five subjects havingpowered patches is significantly lower than the average of the fivecontrols.

Although the specification and Examples above describe aqueous media,the present invention is equally applicable to nonaqueous media such asthe injectable oils familiar to those skilled in the art, such asglycerine, propylene glycol, benzyl alcohol, and the like.

Many other embodiments of this invention will be apparent to thoseskilled in the art, but such will be within the scope of Letters Patentbased on the following claims.

We claim:
 1. An electrolytic transdermal patch including an electricalcircuit with an electrical power source for delivering at least one drugto the bloodstream of the patient comprising in combination:(a) at leastone polypeptide having from about three to about 20 peptide units, and(b) means for transdermal transport of the polypeptide characterized bya current density from about 0.5 microampere/cm² to about 1milliampere/cm² whereby the skin of the patient is neither irritated norerythematized.
 2. A transdermal patch as in claim 1, wherein the meansfor transport comprises a battery, an anode, a cathode, a drugreservoir, and barrier means between electrodes.
 3. A transdermal patchas in claim 2, further comprising a semipermeable membrane on the skinside of the drug reservoir.
 4. A transdemal patch as in claim 1, whereinthe current density of the patch is from about 0.5 ua/cm² to about 10ua/cm².
 5. A transdermal patch as in claim 1, further comprising atleast one compound selected from the group consisting of bufferingagents, chelating agents, antioxidants, preservatives, and biocides. 6.A transdermal patch as in claim 1, further comprising an aqueous solventfor the polypeptide.
 7. A transdermal patch as in claim 6, furthercomprising a dissociating cosolvent.
 8. A transdermal patch as in claim7, wherein the dissociating cosolvent is selected from the groupconsisting of urea, guanidine salt, butanol, 2-butanol, water-solubleamides with more than three carbon atoms, sodium and potassium iodide,sodium perchlorate, sodium butyrate, and any other salt with negativeSetschenow constants.
 9. A transdermal electrolytic patch for deliveringat least one drug directly to the bloodstream of the patient as in claim1, comprising:(a) an active ingredient comprising at least onepolypeptide having from three to twenty peptide units havingpharmacological activity in an application selected from the groupconsisting of alleviating diabetes insipidus, gastrointestinalhemmorhage, induction of childbearing labor, antidiuretic, alleviatingprostate cancer, inhibition of LH-RH FSH, analgesic, hormonalregulation, insulin regulation, growth hormone inhibition, modulation ofblood pressure, regulation of body fluids, and combinations thereof; and(b) electrolytic means for transdermal transport of the polypeptidecharacterized by a current density from about 0.5 microamp/cm² to about1 milliamp/cm², whereby the skin of the patient is neither irritated norerythematized.
 10. A transdermal patch as in claim 9, wherein thepolypeptide is selected from the group consisting of vasopressin,desmopression, oxytocin, bypressin, leuprolide acetate, dynorphin A.dynorphin B, met-enkaphalin, leuenkephalin, thyrotropin, releasinghormone, alphal-melancyte stimulating hormone, beta-melancytestimulating hormone, neurotensin, substance P, somatostatin, angioxensinI, angiotensin II, angiotensin III, atriopeptin, and combinationsthereof.
 11. A transdermal patch as in claim 9, wherein the electrolyticmeans comprises a battery, an anode, a cathode, a drug reservoir, and abarrier means between the electrodes.
 12. A transdermal patch as inclaim 9 further comprising an aqueous solvent for the polypeptide.
 13. Atransdermal patch as in claim 9, further comprising at least onecompound from the group consisting of buffering agents, chelatingagents, antioxidants, preservatives, biocides, and dissociatingcosolvents with a negative Setschenow constant.
 14. A transdermal patchas in claim 9, further comprising current controlling means whereby thecurrent density of the patch is from about 0.5 to about 10microamps./cm².
 15. A transdermal patch as in claim 13, wherein thedissociating cosolvent is selected from the group consisting of urea,alkylderivatives of urea, guanidine salt, butanol, 2-butanol,water-soluble amides with more than three carnon atoms, sodium iodide,potassium iodide, sodium perchlorate, sodium butyrate, and any othersalt with negative Setschenow constants.
 16. A transdermal patch as inclaim 11, further comprising a semipermeable membrane on the skin sideof the drug reservoir.
 17. A transdermal patch for delivering at leastone drug directly to the bloodstream of the patient comprising incombination:(a) a circuit including an electrical power source forsupplying power to and electrically connected to at least one electricalcontact at a drug reservoir and means for controlling the currentdensity of the patch from about 0.5 microampere/cm² to about 10microampere/cm² ; and (b) an active ingredient comprising at least onepolypeptide having from about three to about 20 peptide units in anaqueous drug reservoir;whereby the skin of the patient is neitherirritated nor erythematized.
 18. A transdermal drug patch as in claim17, further comprising a semipermeable membrane on the patient side ofthe drug reservoir.
 19. A transdermal drug patch as in claim 17, furthercomprising at least one compound selected from the group consisting ofbuffering agents, chelating agents, antioxidants, preservatives, andbiocides.
 20. A transdermal drug patch as in claim 17, wherein at leastone polypeptide is LH-RH analog further comprising testosterone.
 21. Atransdermal drug patch as in claim 17, wherein at least one polypeptideis LH-RH analog further comprising Flutamide.
 22. A transdermal drugpatch as in claim 17, further comprising covering means over at leastpart of the drug reservoir.
 23. A transdermal patch as in claim 17,further comprising a water-destructuring agent in the active ingredientin the aqueous drug reservoir.
 24. A transdermal patch as in claim 23,wherein the water-destructuring agent is selected from the groupconsisting of urea, alkylderivatives of urea, guanidine salt, butanol,2-butanol, water-soluble amides with more than three carbon atoms,sodium iodide, potassium iodide, sodium perchlorate, sodium butyrate,any other compound with negative Setschenow constants, and mixturesthereof.
 25. A transdermal drug patch as in claim 24, wherein thewater-destructuring agent is urea.
 26. A transdermal drug patch as inclaim 24, wherein the water-destructuring agent is potassium iodide.